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Downregulation of RNF128 activates Wnt/?-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma.

ABSTRACT: BACKGROUND:Ring finger proteins (RNFs) were involved in carcinogenesis. Here, we aimed to explore the detailed mechanism of RNF128 in the progression of melanoma. METHODS:We reanalyzed several gene expression profiles from the Gene Expression Omnibus (GEO) database and obtained the overlapped differential expressed RNF genes. Among them, RNF128 was selected to further explore its expression, the biological significance, and the underlying molecular mechanism, as well as the clinical relevance in melanoma patients. RESULTS:RNF128 was found to be significantly downregulated in the selected datasets, which was further verified in our melanoma tissues. Moreover, RNF128 downregulation was shown to correlate with the malignant phenotype of melanoma, and further functional assays demonstrated that low levels of RNF128 promoted melanoma progression via inducing cell epithelial-mesenchymal transition (EMT) and the acquisition of stemness. Mechanistically, RNF128 interference activated the Wnt pathway via simultaneously ubiquitinating CD44/cortactin (CTTN), resulting in CD44 and c-Myc transcription, thus revealed that RNF128 participated in a positive feedback of the Wnt pathway-CD44 loop. Clinically, we found that patients expressing low RNF128 and high CD44/CTTN levels had a poor prognosis. CONCLUSION:Downregulated RNF128 activates Wnt signaling to induce cellular EMT and stemness by ubiquitinating and degrading CD44/CTTN, and RNF128 is a reliable diagnostic and prognostic biomarker, and a deeper understanding of RNF128 may contribute to the treatment of melanoma.

SUBMITTER: Wei CY

PROVIDER: S-EPMC6399928 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma.

Wei Chuan-Yuan CY Zhu Meng-Xuan MX Yang Yan-Wen YW Zhang Peng-Fei PF Yang Xuan X Peng Rui R Gao Chao C Lu Jia-Cheng JC Wang Lu L Deng Xin-Yi XY Lu Nan-Hang NH Qi Fa-Zhi FZ Gu Jian-Ying JY

Journal of hematology & oncology 20190304 1

<h4>Background</h4>Ring finger proteins (RNFs) were involved in carcinogenesis. Here, we aimed to explore the detailed mechanism of RNF128 in the progression of melanoma.<h4>Methods</h4>We reanalyzed several gene expression profiles from the Gene Expression Omnibus (GEO) database and obtained the overlapped differential expressed RNF genes. Among them, RNF128 was selected to further explore its expression, the biological significance, and the underlying molecular mechanism, as well as the clinic ...[more]

PMID: 30832692

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Project description:BACKGROUND:Transmembrane 4?L six family member 1 (TM4SF1) is upregulated in several epithelial cancers and is closely associated with poor prognosis. However, the role of TM4SF1 and its potential mechanism in colorectal cancer (CRC) remain elusive. METHODS:We investigated the expression of TM4SF1 in the Oncomine, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of CRC tissues. The effect of TM4SF1 on the epithelial-to-mesenchymal transition (EMT) and cancer stemness of CRC cells was investigated by Transwell, wound healing and sphere formation assays. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which TM4SF1 modulates EMT and cancer stemness in CRC. RESULTS:TM4SF1 expression was markedly higher in CRC tissues than in non-tumour tissues and was positively correlated with poor prognosis. Downregulation of TM4SF1 inhibited the migration, invasion and tumour sphere formation of SW480 and LoVo cells. Conversely, TM4SF1 overexpression significantly enhanced the migration, invasion and tumoursphere formation potential of CRC cells, Additionally, TM4SF1 silencing inhibited the EMT mediated by transforming growth factor-?1 (TGF-?1). Mechanistically, gene set enrichment analysis (GSEA) predicted that the Wnt signalling pathway was one of the most impaired pathways in TM4SF1-deficient CRC cells compared to controls. The results were further validated by WB, which revealed that TM4SF1 modulated SOX2 expression in a Wnt/?-catenin activation-dependent manner. Furthermore, we found that knockdown of TM4SF1 suppressed the expression of c-Myc, leading to decreased c-Myc binding to the SOX2 gene promoter. Finally, depletion of TM4SF1 inhibited metastasis and tumour growth in a xenograft mouse model. CONCLUSION:Our study substantiates a novel mechanism by which TM4SF1 maintains cancer cell stemness and EMT via the Wnt/?-catenin/c-Myc/SOX2 axis during the recurrence and metastasis of CRC.

Dataset Information

Downregulation of RNF128 activates Wnt/?-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma.

Publications

Downregulation of RNF128 activates Wnt/β-catenin signaling to induce cellular EMT and stemness via CD44 and CTTN ubiquitination in melanoma.

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